The long term of these studies is to determine the role of transcription factors of the interferon regulatory factor family (IRF) in immune responses. This application is focused on the clarification of molecular mechanism by which IRF enhance the DNA raised immune response. Over the past years we have identified and characterized three novel IRFs: IRF-3, IRF-5 and IRF-7. These IRF functions as direct transducers of virus induced signaling and play a critical role in induction of the early inflammatory genes. However, their function extends beyond innate immunity and we have identify IRF-7 as a macrophage differentiation factor. Furthermore the expression of IRF-1, IRF-3 or IRF-7 enhances a DNA raised immune response. In the proposed study we wish to examine the molecular basis of the adjuvant effect of IRF on DNA mediated immune response by two viral antigens, hemaglutinin protein of influenza virus and envelope protein of HIV-1. To this effect the study has three Aims in which we shall ask following questions: Aim#1. Is the adjuvant effect of IRF on immune response to two distinct antigens identical? We shall analyzed humeral and cellular response to gp 160 of HIV-1 and compare it with the response to HA of influenza. Aim #2. Is the adjuvant effect of IRF mediated by Type I IFN? The IRF were shown to stimulate induction of Type I IFN we shall therefore examine the adjuvant effect of IRF in mice that is lacking the Type I IFN receptor. Effect of co-expression of IFNa on DNA raised immune response will be examined for comparison. Aim #3. Is there a requirement for IRF activation in the adjuvant effect? We shall examine the adjuvant effect of constitutively active IRF-3 and !RF-7 on a profile of DNA mediate immune responses. Significance: Compared to the conventional vaccines, the DNA mediated vaccination provides elicits potent virus specific CD4+ and CD8+ responses that are critical for controlling viremia in many viral infections including HIV-1 and its distribution would be easy and economical. Thus the development of potent adjuvant of DNA elicited immune response is of great epidemiological and economical importance.